Statement regarding federally sponsored research or development

ABSTRACT

A process for labeling organic compounds with deuterium and tritium is described using specific catalysts.

RELATED APPLICATIONS

[0001] This application is related to U.S. Serial No. 60/278,283, filedMar. 22, 2001, the contents of which are hereby incorporated byreference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with U.S. Government support under Grant(Contract) No. DE-AC03-76F00098 awarded by The U.S. Department of Energyfor the operation of Ernest Orlando Lawrence Berkeley NationalLaboratory. The U.S. Government has certain rights to this invention.

BACKGROUND OF THE INVENTION

[0003] Deuterium-labeled and tritium-labeled organic and organometalliccompounds are used widely in spectroscopic experiments and in studiesaimed at the elucidation of chemical structure and reaction mechanisms.These materials are expensive because they must be prepared by HIDexchange from unlabeled starting materials, often in multi-sequenceprocedures that require a more common compound to serve as a source ofdeuterium that can be transferred into the molecule of interest. Usingclassical methods it is usually easiest to exchange deuterium withso-called “activated” protons (e.g., protons that are acidic, orsusceptible to electrophilic exchange using strong acids); exchange with“unactivated” protons is much more difficult. As a result, manydeuterium-labeled compounds are either expensive or not availablecommercially. The present invention relates to a process for thepreparation of a deuterated and/or tritiated compound which is useful asa raw material for pharmaceuticals, agricultural chemical, functionalmaterials, analytical tracers and similar uses. When reference is madeto deuterium and deuteration it is intended to include also tritium andtritiation, or a mixture of deuterium and tritium.

[0004] To make deuterium-labeled and tritium labeled organic andorganometallic materials less expensively and more readily available,the chemical community requires a universal (preferably catalytic)method that would allow H/D exchange from an inexpensive deuterium andtritium source into a wide range of proton-containing compounds. Thedeuterium and tritium source that fits these criteria ideally is D₂O andT₂O, due to their low cost and low toxicity.

REVIEW OF THE PRIOR ART

[0005] U.S. Pat. No. 3,510,519 to Frejaville et al. relates to thepreparation of deuterated compounds by contacting and reacting undernon-turbulent countercurrent flow conditions two compounds wherein oneof the compounds is in liquid form and the other is in gaseous form.Frejaville et al. rely on a greatly elongated uncatalyzed reaction zoneto achieve H-D exchange.

[0006] U.S. Pat. No. 3,989,705 describes a process for the deuteriationof organic substrates by hydrogen substitution using a strong acid andhigh temperatures.

[0007] U.S. Pat. No. 3,900,557 to Strathdee describes a catalystcomprising a transition metal coordination complex anchored on across-linked polystyrene. The anchored catalyst is useful for promotingH-D exchange between deuterated forms of hydrogen-containing gas streamsand liquid water or alcohols.

[0008] U.S. Pat. No. 4,421,865 describes a process for deuteratingcompounds using a porous ion exchange resin.

[0009] U.S. Pat. No. 5,149,820 describes deuterated aromatic aldehydesused for anti-cancer drugs.

[0010] U.S. Pat. No. 5,186,868 describes methods for tritium labelingcomprising reacting an organic solvented solution of alkali metal alkylwith a tritium gas in the presence of an alkyl tertiary amine.

[0011] U.S. Pat. No. 5,733,984 describes a process for the preparationof a deuterated compound comprising treating an organic compound inheavy water under high-temperature and high-pressure conditions not lessthan the subcritical temperature and subcritical pressure.

[0012] U.S. Pat. No. 5,830,763 describes a process for producing adeuterated compound comprising heating a deuterium oxide solution at aspecific pH and at a temperature and pressure so that a supercriticalreaction mass forms.

[0013] The above U.S. Patents are hereby incorporated by reference intheir entirety.

BRIEF SUMMARY OF THE INVENTION

[0014] In an important step toward the solution of the problemsdescribed in the paragraphs above, the inventors have surprisinglydiscovered a class of transition metal catalysts that catalyze theexchange of deuterium from D₂O into a wide range of organic andorganometallic compounds that are otherwise difficult to deuterate.Exchange occurs with both traditionally “activated” and “unactivated”hydrogens. The most active catalysts of this invention have been foundto be [Cp*(PMe₃)IrH₃][OTf] and Cp*(PMe₃)IrCl₂, but this inventioncontemplates that any organometallic catalyst having the general formuladescribed herein below is suitable. The latter catalyst is air stable,and is prepared in two high-yielding steps from commercially availableIrCl₃-3H₂O.

[0015] The preparative advantages of these catalysts include theirfacile removal from products and their stability toward air and water.In contrast to related catalysts based on platinum that have beenreported to act similarly, the use of strongly acidic conditions is notnecessary, and their activity is higher than that of previously reportedrhodium and iridium complexes. The H/D exchange according to the instantinvention occurs under moderate conditions. Water typically participatesin H/D exchange only with activated hydrogens, which would lead one tobelieve that the instant invention would not work efficiently;surprisingly the inventors have found two catalyst compositions that dowork. Water often causes organometallic compounds to decompose, whichwould also lead one to believe that the instant invention would not workefficiently. Again however, the inventors have surprisingly foundcatalyst compositions that will work in an aqueous environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The structures of the transition metal complexes that serve ascatalysts in the deuteration or tritiation exchange process according tothe instant invention are described below. The structures of a type ofcatalyst of this invention are shown below along with the examplestructures for Cp*(PMe₃)IrCl₂ and [Cp*(PMe₃)IrH₃][OTf], which are twospecies shown to have good activity for hydrogen/deuterium andhydrogen/tritium exchange.

[0017] A₁ and A₂ are meant to represent any ligand that can donate 6electrons in the ionic counting scheme (described below, also known asthe ionic model). A₁ and A₂ may also independently represent two groupsthat are fused, linked or bonded together and together the resultantcombination of the two add contribute six electrons, for example anallyl and alkene. L₁ and L₂ are meant to represent a two-electron donorin the ionic counting scheme. Non-limiting examples of ligands thatfunction adequately for A₁ and A₂ include cyclopentadienide,pentamethylcyclopentadienide, (η⁵:η¹-(Me₂P(CH₂SiMe₂)C₅Me₄) andhydridotris(3,5-dimethylpyrazolyl)borate. L₁ and L₂ can be atrimethylphosphine, triphenylphosphine, tertbutylisonitrile, NH₂tBu, OH₂or PF₃. X₁, X₂, X₃, X₄ and X₅ are independently or the same, and aremeant to represent a two electron donor in the ionic counting scheme,which include species of Cl, Br, H, CH₂Cl₂ and OTf. M is a transitionmetal chosen from the group consisting of Co, Rh and Ir. Preferred isIr. Y is an anion capable of rendering the compound charge neutral. Nonlimiting examples include OTf, B(C₆F₅)₃Me, NO₃, ClO₄, SbF₆, BPh₄, AlCl₄.Cp* is substituted cyclopentadienide, Me₃ is trimethyl and OTf isOSO₂CF₃. In this specification, tBu stands for a tert-butyl group, Phstands for a phenyl group, which may be substituted or unsubstituted andMe stands for methyl. Cp stands for cyclopentadienide and thecyclopentadienide ring may be substituted or unsubstituted. It iscontemplated that substitution may occur independently at each positionof the ring. Substitution moieties include an alkyl group of 1-20 carbonatoms, such as 1-5 methyl groups, for examplepentamethylcyclopentadienyl, hydrogen atoms, halogen atoms, substitutedor unsubstituted aryl groups, a substituted or unsubstituted silylgroup, an alkoxy group, an aryloxy group or a substituted or anunsubstituted amino group.

[0018] In another embodiment of the invention it is contemplated thatthe structure of the transition metal complex that serves as a catalystin the deuteration or tritiation exchange process is as shown below:

[0019] where M is selected from the group consisting of Fe, Ru and Os;

[0020] A₃ and A₄ each independently represent ligands that are a 6electron donor;

[0021] L₃ and L₄ each independently represent ligands that are a 2electron donor;

[0022] X₈, X₉, X₁₀ and X₁₁ each independently represent ligands that area two electron donor.

[0023] In yet another embodiment of the invention it is contemplatedthat the structure of the transition metal complex that serves as acatalyst in the deuteration or tritiation exchange process is as shownbelow:

[0024] where M is selected from the group consisting of Ni, Pd and Pt;

[0025] A₅ and A₆ each independently represent ligands that are a 6electron donor;

[0026] L₅ and L₆ each independently represent ligands that are a 2electron donor;

[0027] X₁₂ represents ligands that are a two electron donor;

[0028] and Y is an anion capable of creating a charge neutral complex.

[0029] For the type III-VI catalysts described above, A₃₋₆ are meant torepresent any ligand that can donate 6 electrons in the ionic countingscheme (described below, also known as the ionic model). A₃₋₆ may alsoindependently represent two groups that are fused, linked or bondedtogether and together the resultant combination of the two addcontribute six electrons, for example an allyl and alkene. L₃₋₆ aremeant to represent a two-electron donor in the ionic counting scheme.Non-limiting examples of ligands that function adequately for A₃₋₆include cyclopentadienide, pentamethylcyclopentadienide, (η⁵:η¹-(Me₂P(CH₂SiMe₂)C₅Me₄) and hydridotris(3,5-dimethylpyrazolyl)borate.L₃₋₆ can be a trimethylphosphine, triphenylphosphine,tertbutylisonitrile, NH₂tBu, OH₂ or PF₃. X₈₋₁₂ are independently or thesame and are meant to represent a two electron donor in the ioniccounting scheme, which include species of Cl, Br, H, CH₂Cl₂ and OTf. Mis a transition metal chosen from the group consisting of Fe, Ru and Osfor the type III and IV catalyst and from the group consisting of Ni, Pdand Pt for the type V and type VI catalyst. Y is an anion capable ofrendering the compound charge neutral. This may be OTf, B(C₆F₅)₃Me, NO₃,ClO₄, SbF₆, BPh₄, AlCl₄. Cp* is substituted cyclopentadienide, Me₃ istrimethyl and OTf is OSO₂CF₃. Cp stands for cyclopentadienide and thecyclopentadienide ring may be substituted or unsubstituted. It iscontemplated that substitution may occur independently at each positionof the ring. Substitution moieties include an alkyl group of 1-20 carbonatoms, such as 1-5 methyl groups, for examplepentamethylcyclopentadienyl, hydrogen atoms, halogen atoms, substitutedor unsubstituted aryl groups, a substituted or unsubstituted silylgroup, an alkoxy group, an aryloxy group or a substituted or anunsubstituted amino group.

[0030] When reference is made to deuterium and deuteration it isintended to include also tritium and tritiation, or a mixture ofdeuterium and tritium. This means that the catalysts described hereinare useful for both deuteriation and tritiation.

[0031] When reference is made to moderate conditions, these aregenerally described in the art as pH neutral and a temperature of lessthan about 200° C.

[0032] When reference is made to organic substrate, it is meant anycomposition containing carbon capable undergoing deuteration ortritiation.

[0033] When reference is made to contacting, it is meant to include allmethods and mediums, including all phases of matter, in which theorganic substrate and/or catalyst and/or deuterium or tritium source arebrought either together or in such proximity to one another such thatthe catalyst of this invention may have a catalytic effect.

[0034] When reference is made to medium, it is meant the solvent of theprocess described herein. The solvent of the process described herein isgenerally water or D₂O. However, a solvent mixture of D₂O and CD₃CO₂D isalso within the range of instant invention. Thus it is clear that thisprocess can be run at a pH of between about 1 and 7, depending on thesolvent used.

[0035] When reference is made to “contribute 6 electrons” it is to beknown that the counting is done according to the ionic model it is meantthat there are 6 electrons in the bond between the ligand and metal. Thesame meaning is attached to the phrase “6 electron donor”. The samemeaning is attached to the phrase “contribute 2 electrons” or “2electron donor”, except of course with a different number of electrons.

[0036] When reference is made to a polar solvent, polarity is measuredby the standard method and the dielectric constant episilon is greaterthan 20. Water has an epsilon value of 78.

[0037] When reference is made to deuterium labeled compounds or tritiumlabeled compounds, it is meant a compound having at least one ordinary Hatom substituted with deuterium or tritium. Deuterium is an isotope of Hwhose nucleus contains a proton and a neutron. The symbol D may be usedfor deuterium and D₂O may be referred to as deuterium oxide or heavywater, and can be obtained by electrolysis of ordinary water. Tritium isan isotope of H whose nucleus contains a proton and two neutrons. It isradioactive and is often given the symbol T. Deuterium labeled compoundand tritium labeled compounds as referred to herein also includescoordination-sphere isomers, linkage isomers, geometrical isomers andoptical isomers thereof.

[0038] When reference is made to the hydride ion, it is meant a H atomthat has picked up one electron to form H.

[0039] When reference is made to ligands, it is meant that to includebroadly the molecules or ions that surround a metal ion in the catalystcomplex. They may be monodentate or polydentate, be cations, anions orpolar molecules, have any number of unshared valence electrons andparticipate in any type of bonding or coupling inteaction. Ligand orligands is also meant to include two species that may be fused or bondedor linked that cooperate to contribute to the coorrdination catalyst. Anexample of a catalyst using two species linked together is shown below:

[0040] When reference is made to resistant to ligand redistribution, itis meant that A_(x) and L_(x), where x=1−6, are not labile, i.e. they donot dissociate from the metal during the catalytic process.

[0041] When reference is made to deuterium and deuteration it isintended to include also tritium and tritiation, or a mixture ofdeuterium and tritium.

[0042] When reference is made to substrate or organic substrate, it ismeant the organic compound that is subject to deuteration and/ortritiation.

[0043] When reference is made to system, it is meant to include thefunctional catalyst as it is being used in the process claimed herein.

[0044] The structures of these transition metal complexes are furtherdescribed below. The first complex, a type I complex, and representedfor illustration purposes by, Cp*(PMe₃)IrCl₂, is a charge neutralcomplex, in the sense that the three “anionic” groups (the Cp* and twochloride ligands) are covalently bonded to the iridium center. That is,they are within the inner coordination sphere of the transition metal.While not wishing to be bound by any particular theory, it is believedthat the mechanism of action of this catalyst on the organic substrateproceeds by dissociation of a chloride ligand to produce a cationiciridium center, [Cp*(PMe₃)IrCl][Cl]with an outer-sphere chloride ligand.So, it is believed the active species to be an iridium (III) cation, andthat the polar nature of the medium is critical to the catalyst'ssuccess.

[0045] Electronically, this complex may be described as having 18electrons, which may be distributed to the various constituents, (theionic counting method). Ionic counting convention requires that ligandsare anionic or cationic and that the oxidation state of the metal isappropriate for the realistic distribution of electrons. In the ioniccounting scheme, the iridium is said to be oxidized by the Cp* and 2chloride ligands, and is therefore iridium (III), carrying 6 delectrons. The Cp* therefore donates 6, the two chlorides donate twoapiece, and the phosphine (L type ligand) donates 2, giving a total of18 electrons. This is because when the Cl dissociates, it dissociates asa chloride.

[0046] Note that the mechanism of action of the type I and II catalystsis believed to be the same. While not wishing to be bound by anyparticular theory, it is believed that the salt-like species[Cp*(PMe₃)IrH₃][OTf], the type II complex, by illustration, is composedof discrete cations and anions, but the degree of association of theseions will of course be solvent dependent. That is, the more polar thesolvent, the more the ions are dissociated. Electronically, this complexalso has 18 electrons, and in the ionic counting scheme we have aniridium (V) species, having 4 d electrons. Each hydride ligand donates 2electrons, the Cp* donates 6 electrons, the phosphine donates 2electrons, and there is an overall positive charge on the complex. Itappears that the mechanism of this catalyst begins with dihydrogenelimination to give an iridium (III) cation, [Cp*(PMe₃)IrH][OTf].

[0047] Mechanistically, the type I and II catalysts are assumed to forma 16 electron catalytically active species, by either dissociating aligand (ionizing in the case of type I) or reductively eliminating aligand (a small molecule such as dihydrogen, in the case of type II).

[0048] Any organic or organometallic compound can be used as an organicsubstrate to be deuterated or tritiated by the catalysts of the presentinvention. Preferred examples of organic compounds include aliphaticcompounds, alicyclic compounds, aromatic hydrocarbons and polymericcompounds such as plastics, rubbers and proteins. Specific examples ofthe alicyclic compounds include cyclohexane, methyl cyclohexane,pyridine and tetrahydrofuran. Specific examples of the aromatichydrocarbons include benzene, toluene, ethylbenzene, xylene,bromobenzene, chlorobenzene, dichlorobenzene, nitrobenzene, phenol,hydroquinone, benzoic acid, salicylic acid, phthalic acid and aniline.

[0049] Preferably the catalysts according to the instant invention areorganometallic in nature; the most active have been found to be[Cp*(PMe₃)IrH₃][OTf] and Cp*(PMe₃) IrCl₂, where Cp* ispentamethylcyclopentadienide, Me₃ is trimethyl and OTf is OSO₂CF₃. Thelatter catalyst is air stable, and is prepared in two high-yieldingsteps from commercially available IrCI₃-3H₂O.

[0050] The type I-VI catalysts described by this invention can beprepared according to methods known in the art. For example, Cp*(PMe₃)IrCl₂ can be prepared according to the methods described in J. C. S.Dalton Trans., pp. 2003-8, (1981) and hereby incorporated by referencein its entirety. [Cp*(PMe₃)IrH₃][OTf] can be prepared according to themethods described in Organometallics, 1992, 11, 231-237 and herebyincorporated by reference in its entirety. Other synthetic routes aredisclosed in J. Am. Chem. Soc. 1997, 119, 11028-11036, “Synthesis andCharacterization of Hydrotris(pyrazolyl)borate Dihydrogen/HydrideComplexes of Rhodium and Iridium”. This reference is hereby incorporatedby reference in its entirety.

[0051] The temperature that the deuteration and/or tritiation isaccomplished can be anywhere in the range of from 75 to 200 degreescentigrade. Preferably the temperature is about 100-150 and morepreferably the temperature is between about 130-140° C.

[0052] A typical method of deuterating is described next. The reactionscheme is shown below.

[0053] R represents any organic molecule. A J. Young-style NMR tube wascharged with a type I catalyst, Cp*(PMe₃)IrCl₂, an organic substrate,D₂O (0.5 mL), and an external standard capillary (vide infra) consistingof 1, 3, 5-trimethoxybenzene dissolved in C₆D₆. The tube was thenclosed, and reaction progress was monitored by ¹H NMR spectroscopythrough loss of intensity of the organic substrate resonances. Thedeuteration level is calculated by dividing the standardized integrationof the starting organic compound before heating by the measuredstandardized integration after heating at 135° C. first at 18 h and thenat 40 h. ²H NMR spectroscopy was used as a qualitative tool todemonstrate the presence of deuterium in the incorporation for thesubstrate sodium octanoate were further confirmed by isolating thecorresponding acid after acidic workup and extraction into diethyl ether(80% recovery) and checking the ¹H NMR integrations against the internalstandard 1,3,5-trimethoxybenzene. The process is completed when one ormore deuterium atoms exchanges with one or more protons of the organicsubstrate molecule. The now deuterium-tagged organic molecule can beseparated or isolated by techniques readily available to one of ordinaryskill in the art. Methods and results for determining the amount ofdeuteration or tritiation are fully described in J. Am. Chem. Soc. 124,2092-2093, the contents of which are hereby incorporated by reference intheir entirety.

[0054] The external standard capillaries were prepared by first flamesealing one end of a 9-inch Pasteur pipette. The pipette was then filledto a level of approximately 5 cm with a solution prepared fromapproximately 200 mg 1, 3, 5-trimethoxybenzene and 2 nL C₆D₆. Thecapillaries were then sealed under partial vacuum with the aid of apipette bulb. Because no exchange was observed to occur at roomtemperature, the samples containing these capillaries could becalibrated by ¹H NMR spectroscopy before heating. The deuteration levelsfor the substrates reported herein were shown to be reproducible towithin 5-10% by this method. For an example of NMR spectroscopy as amethod of determining deuterium incorporation, see Lenges,C. P.: White,P. S.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 346, the contents ofwhich are hereby incorporated by reference in their entirety.

[0055] The present invention will be described in detail with referenceto the following Examples, but the invention should not be construed asbeing limited thereto.

EXAMPLE 1

[0056] A glass vessel was charged with 6.0 mg (0.013 mmol)Cp*(PMe₃)IrCl₂, 0.500 mL (27.6 mmol) D₂O, and 20 μL (0.247 mmol)tetrahydrofuran (THF), and an external standard capillary consisting of1, 3, 5-trimethoxybenzene dissolved in C₆D₆. The vessel was sealed andthe reaction mixture was heated to 135° C. for 43 h. Using ¹H NMRspectroscopy, it was determined that the α-position of THF had beendeuterium labeled to the extent of 89%, and the β-position had beenlabeled to the extent of 40%. The labeled tetrahydrofuran may beseparated from the water by extraction with diethyl ether solvent.Distillation will enable the isolation of the pure labeledtetrahydrofuran. It was found that performing this procedure under anitrogen atmosphere and an air atmosphere led to identical deuteriumincorporation results.

EXAMPLE 2

[0057] A glass vessel was charged with 3.2 mg (0.0068 mmol)Cp*(PMe₃)IrCl₂, 0.500 mL (27.6 mmol) D₂O, and 14.2 μL (0.135 mmol)diethyl ether, and an external standard capillary consisting of 1, 3,5-trimethoxybenzene dissolved in C₆D₆. The vessel was sealed and thereaction mixture was heated to 135° C. for 50 h. Using ¹H NMRspectroscopy, it was determined that the α-position of diethyl ether hadbeen deuterium labeled to the extent of 16%, and the β-position had beenlabeled to the extent of 55%. Distillation would enable isolation of thepure labeled diethyl ether.

EXAMPLE 3

[0058] A glass vessel was charged with 4.7 mg (0.0085 mmol)[Cp*(PMe₃)IrH₃][OTf], 0.500 mL (27.6 mmol) D₂O, and 20.7 mg (0.169 mmol)benzoic acid. The vessel was sealed and the reaction mixture was heatedto 135° C. for 40 h. The reaction mixture within the vessel was thenextracted with 3×2 mL diethyl ether and filtered through silica gel.Mass spectrometric analysis of the resulting solution indicated that theoverall deuterium incorporation for the H/D exchange process was 80%.

EXAMPLE 4

[0059] A glass vessel was charged with 6.1 Mg (0.011 mmol)[Cp*(PMe₃)IrH₃][OTf], 0.500 mL (27.6 mmol) D₂O, and 20 μL (0.173 mmol)tetrahydrofuran (THF). The vessel was sealed and the reaction mixturewas heated to 135° C. for 48 h. Using ¹H NMR spectroscopy, it wasdetermined that the α-position of TBF had been deuterium labeled to theextent of 86%, and the β-position had been labeled to the extent of 35%.The labeled tetrahydrofuran was separated from the water by extractionwith diethyl ether solvent.

EXAMPLE 5

[0060] A glass vessel was charged with 5.0 mg (0.0067 mmol)[Cp*(PPh₃)IrH₃][OTf], 0.500 mL (27.6 mmol) D₂O, and 20 μL (0.173 mmol)tetrahydrofuran (THF). The vessel was sealed and the reaction mixturewas heated to 135° C. for 4 h. Using ¹H NMR spectroscopy, it wasdetermined that the α-position of THF had been deuterium labeled to theextent of 25%, and the β-position had been labeled to the extent of 22%.

EXAMPLE 6

[0061] A glass vessel was charged with 6.1 mg (0.0087 mmol)Cp*(PMe₃)Ir(OTf)₂, 0.500 mL (27.6 mmol) D₂O, and 20 μ(0.247 mmol)tetrahydrofuran (TBF), and an external standard capillary consisting of1, 3, 5-trimethoxybenzene dissolved in C₆D₆. The vessel was sealed andthe reaction mixture was heated to 135° C. for 59 h. Using ¹H NMRspectroscopy, it was determined that the β-position of TBF had beendeuterium labeled to the extent of 63%, and the β-position had beenlabeled to the extent of 30%.

EXAMPLE 7

[0062] A glass vessel was charged with 5.3 mg (0.0095 mmol)[Cp*(PMe₃)IrH₃)][OTf], 0.250 mL (27.6 mmol) D₂O, 0.250 mL CD₃CO₂D, and20 μL (0.173 mmol) tetrahydrofuran (THF). The vessel was sealed and thereaction mixture was heated to 135° C. for 14 h. Using ¹H NMRspectroscopy, it was determined that the α-position of THF had beendeuterium labeled to the extent of 94%, and the β-position had beenlabeled to the extent of 40%.

EXAMPLE 8

[0063] A glass vessel was charged with 6.4 mg (0.013 inmol)Cp*(PMe₃)IrBr₂, 0.500 mL (27.6 mmol) D₂O, and 17 μL (0.227 mmol)n-propanol, and an external standard capillary consisting of 1, 3,5-trimethoxybenzene dissolved in C₆D₆. The vessel was sealed and thereaction mixture was heated to 135° C. for 40 h. Using ¹H NMRspectroscopy, it was determined that the (α-position had been deuteriumlabeled to the extent of 58%, the β-position had been labeled to theextent of 39%, and the γ-position had been labeled to the extent of 60%.The labeled n-propanol was separated from the water by extraction withdiethyl ether solvent.

EXAMPLE 9

[0064] A glass vessel was charged with 6.9 mg (0.014 mmol)[Cp*(PMe₃)Ir(OH₂)₂][SO₄], 0.500 mL (27.6 mmol) D₂O, and 14.2 μL (0.135mmol) diethyl ether, and an external standard capillary consisting of 1,3, 5-trimethoxybenzene dissolved in C₆D₆. The vessel was sealed and thereaction mixture was heated to 135° C. for 42 h. Using ¹H NMRspectroscopy, it was determined that the α-position of diethyl ether hadbeen deuterium labeled to the extent of 29%, and the β-position had beenlabeled to the extent of 72%.

EXAMPLE 10

[0065] A glass vessel was charged with 6.9 mg (0.014 mmol)(η⁵:η¹-(Me₂P(CH₂SiMe₂)C₅Me₄)Ir(OSO₂CF₃)₂, 0.500 mL (27.6 mmol) D₂O, and20.6 μL (0.196 mmol) diethyl ether, and an external standard capillaryconsisting of 1, 3, 5-trimethoxybenzene dissolved in C₆D₆. The vesselwas sealed and the reaction mixture was heated to 135° C. for 40 h.Using ¹H NMR spectroscopy, it was determined that the α-position ofdiethyl ether had been deuterium labeled to the extent of 19%, and theβ-position had been labeled to the extent of 42%.

EXAMPLE 11

[0066] A glass vessel was charged with 5.7 mg (0.0099 mmol)[(η⁵:η¹-(Me₂P(CH₂SiMe₂)C₅Me₄)Ir(OH₂)₂][SO₄], 0.500 mL (27.6 mmol) D₂O,and 20.7 μL (0.197 mmol) diethyl ether, and an external standardcapillary consisting of 1, 3, 5-trimethoxybenzene dissolved in C₆D₆. Thevessel was sealed and the reaction mixture was heated to 135° C. for 40h. Using ¹H NMR spectroscopy, it was determined that the α-position ofdiethyl ether had been deuterium labeled to the extent of 31%, and theβ-position had been labeled to the extent of 46%.

EXAMPLE 12

[0067] A glass vessel was charged with 14.6 mg (0.034 mmol) Cp*(NH₂^(t)Bu)IrCl₂, 0.500 mL (27.6 mmol) D₂O, and 70.5 μL (0.672 mmol) diethylether, and an external standard capillary consisting of 1, 3,5-trimethoxybenzene dissolved in C₆D₆. The vessel was sealed and thereaction mixture was heated to 135° C. for 40 h. Using ¹H NMRspectroscopy, it was determined that the overall deuterium incorporationfor diethyl ether was 25%.

EXAMPLE 13

[0068] A glass vessel was charged with 5.2 mg (0.011 mmol)Cp*(PF₃)IrCl₂, 0.500 mL (27.6 mmol) D₂O, and 50.0 μL (0.428 mmol)diethyl ether, and an external standard capillary consisting of 1, 3,5-trimethoxybenzene dissolved in C₆D₆. The vessel was sealed and thereaction mixture was heated to 135° C. for 40 h. Using ¹H NMRspectroscopy, it was determined that the overall deuterium incorporationfor diethyl ether was 14%.

EXAMPLE 14

[0069] A glass vessel was charged with 7.5 mg (0.016 mmol)Cp*(PMe₃)IrCl₂, 0.500 mL (27.6 mmol) D₂O, 15.4 mg (0.0789 mmol) YCl₃,and 23.6 μL (0.316 mmol) n-propanol, and an external standard capillaryconsisting of 1, 3, 5-trimethoxybenzene dissolved in C₆D₆. The vesselwas sealed and the reaction mixture was heated to 135° C for 40 h. Using¹H NMR spectroscopy, it was determined that the α-position had beendeuterium labeled to the extent of 35%, the β-position had been labeledto the extent of 29%, and the γ-position had been labeled to the extentof 29%. The labeled n-propanol was separated from the water byextraction with diethyl ether solvent.

EXAMPLE 15

[0070] A glass vessel was charged with 9.0 mg (0.012 mmol) Tp^(Me2)(PMe₃)IrBr₂ (Tp^(Me2)=hydridotris(3,5-dimethylpyrazolyl)borate),0.500 mL (27.6 mmol) D₂O, and 18.6 μL (0.248 mmol) n-propanol, and anexternal standard capillary consisting of 1, 3, 5-trimethoxybenzenedissolved in C₆D₆. The vessel was sealed and the reaction mixture washeated to 135° C. for 40 h. Using ¹H NMR spectroscopy, it was determinedthat the α-position had been deuterium labeled to the extent of 40%, theβ-position had been labeled to the extent of 39%, and the γ-position hadbeen labeled to the extent of 58%. The labeled n-propanol was separatedfrom the water by extraction with diethyl ether solvent.

[0071] Although the foregoing invention has been described in somedetail for purposes of clarity of understanding, those skilled in theart will appreciate that various adaptations and modifications of thejust described preferred embodiments can be configured without departingfrom the scope and spirit of the invention. Therefore, the describedembodiments should be taken as illustrative and not restrictive, and theinvention should not be limited to the details given herein but shouldbe defined by the following claims and their full scope of equivalents.

We claim:
 1. A method of preparing a deuterium labeled or tritiumlabeled compound comprising contacting an organic substrate with acatalyst having the at least one of the following structures:

where M is selected from the group consisting of Co, Rh or Ir; A₁ and A₂each independently represent ligands that are a 6 electron donor; L₁ andL₂ each independently represent ligands that are a 2 electron donor; X₁,X₂, X₃, X₄ and X₅ each independently represent ligands that are a twoelectron donor; Y is an anion capable of creating a charge neutralcomplex, and contacting the organic substrate and said catalyst with asource of deuterium or tritium and heating the combination at atemperature of from 75-200° C.
 2. A method of preparing a deuteriumlabeled or tritium labeled compound according to claim 1, wherein thecatalyst has the following formula: [Cp*(PMe₃)IrH₃][OTf],where Cp* ispentamethylcyclopentadienide, Me is methyl and OTf is OSO₂CF₃.
 3. Amethod of preparing a deuterium labeled or tritium labeled compoundaccording to claim 1, wherein the catalyst has the following formula:Cp*(PMe₃)IrCl₂,where Cp* is pentamethylcyclopentadienide and Me ismethyl.
 4. A method of preparing a deuterium labeled or tritium labeledcompound according to claim 1, where A₁ and A₂ arepentamethylcyclopentadienide.
 5. A method of preparing a deuteriumlabeled or tritium labeled compound according to claim 1, wherein thesource of deuterium is D₂O.
 6. A method of preparing a deuterium labeledor tritium labeled compound according to claim 1, wherein the source oftritium is T₂O.
 7. A method of preparing a deuterium labeled or tritiumlabeled compound according to claim 1, wherein the combination is heatedat a temperature of from 100-150° C.
 8. A method of preparing adeuterium labeled or tritium labeled compound according to claim 7,wherein the combination is heated at a temperature of from 130-140° C.9. A method of preparing a deuterium labeled or tritium labeled compoundaccording to claim 1, wherein: A₁ and A₂ each independently are selectedfrom the group consisting of cyclopentadienide,pentamethylcyclopentadienide, (η⁵:η¹-(Me₂P(CH₂SiMe₂) C₅Me₄) andhydridotris(3,5-dimethylpyrazolyl)borate; L₁ and L₂ each independentlyare selected from the group consisting of trimethylphosphine,triphenylphosphine, tertbutylisonitrile, NH₂tBu, OH₂ or PF₃; X₁, X₂, X₃,X₄, and X₅ are independently selected from the group consisting of Cl,Br, H, CH₂Cl₂ and OTf; M is a transition metal chosen from the groupconsisting of Co, Rh and Ir, and Y is an anion selected from the groupconsisting of OTf and B(C₆F₅)₃Me.
 10. A method of preparing a deuteriumlabeled or tritium labeled compound according to claim 9, wherein M isIr.
 11. A method of preparing a deuterium labeled or tritium labeledcompound according to claim 1, wherein said catalyst is resistant toligand redistribution.
 12. A method of preparing a deuterium labeled ortritium labeled compound according to claim 1, wherein A₁ and L₁ or A₂and L₂ are fused or linked to contribute a total of 8 electrons.
 13. Adeuterated or tritiated compound produced by the method of claim
 1. 14.A method of preparing a deuterium labeled or tritium labeled compoundcomprising contacting an organic substrate with a catalyst having atleast one of the following structures:

where M is selected from the group consisting of Fe, Ru and Os; A₃ andA₄ each independently represent ligands that are a 6 electron donor; L₃and L₄ each independently represent ligands that are a 2 electron donor;X₈, X₉, X₁₀, and X₁₁, each independently represent ligands that are atwo electron donor; and contacting the organic substrate and saidcatalyst with a source of deuterium or tritium and heating thecombination at a temperature of from 75-200° C.
 15. A method ofpreparing a deuterium labeled or tritium labeled compound according toclaim 1, where A₃ and A₄ are pentamethylcyclopentadienide.
 16. A methodof preparing a deuterium labeled or tritium labeled compound accordingto claim 14, wherein the source of deuterium is D₂O.
 17. A method ofpreparing a deuterium labeled or tritium labeled compound according toclaim 14, wherein the source of tritium is T₂O.
 18. A method ofpreparing a deuterium labeled or tritium labeled compound according toclaim 14, wherein the combination is heated at a temperature of from100-150° C.
 19. A method of preparing a deuterium labeled or tritiumlabeled compound according to claim 14, wherein the combination isheated at a temperature of from 130-140° C.
 20. A method of preparing adeuterium labeled or tritium labeled compound according to claim 14,wherein said catalyst is resistant to ligand redistribution.
 21. Amethod of preparing a deuterium labeled or tritium labeled compoundcomprising contacting an organic substrate with a catalyst having atleast one of the following structures:

where M is selected from the group consisting of Ni, Pd and Pt; A₅ andA₆ each independently represent ligands that are a 6 electron donor; L₅and L₆ each independently represent ligands that are a 2 electron donor;X₁₂ represents ligands that are a two electron donors; Y is an anioncapable of creating a charge neutral complex, and contacting the organicsubstrate and said catalyst with a source of deuterium or tritium andheating the combination at a temperature of from 75-200° C.
 22. A methodof preparing a deuterium labeled or tritium labeled compound accordingto claim 21, where A₅ and A₆ are pentamethylcyclopentadienide.
 23. Amethod of preparing a deuterium labeled or tritium labeled compoundaccording to claim 21, wherein the source of deuterium is D₂O.
 24. Amethod of preparing a deuterium labeled or tritium labeled compoundaccording to claim 21, wherein the source of tritium is T₂O.
 25. Amethod of preparing a deuterium labeled or tritium labeled compoundaccording to claim 21, wherein the combination is heated at atemperature of from 100-150° C.
 26. A method of preparing a deuteriumlabeled or tritium labeled compound according to claim 21, wherein thecombination is heated at a temperature of from 130-140° C.
 27. A methodof preparing a deuterium labeled or tritium labeled compound accordingto claim 21, wherein said catalyst is resistant to ligandredistribution.